Familial Thoracic Aortic Aneurysm and Aortic Dissection (TAAD) Panel (9 Genes) Test Details
Familial thoracic aortic aneurysm and aortic dissection (TAAD) is inherited in an autosomal-dominant pattern with up to 20% of individuals with TAAD having an affected first-degree relative (Milewicz 2006). The age of onset and rate of progression of aortic dilation are highly variable even within families. In TAAD, the aorta becomes weakened and stretched and may lead to a sudden tearing or aneurysm. Both aortic aneurysms and dissections greatly increase the risk that the aorta will rupture causing life-threatening internal bleeding. Other features of TAAD may include brain or abdominal aneurysms, congenital heart defects, inguinal hernias, scoliosis, or a purplish skin discoloration (livedo reticularis) caused by abnormalities in dermal capillaries. For more information on TAAD, please visit GeneReviews.
Aortic aneurysms and dissections are estimated to cause almost 30,000 deaths per year in the US and familial TAAD is estimated to be responsible for 20% of these deaths due to variants in one of several genes. Of individuals with TAAD, approximately 14% have pathogenic variants in ACTA2, and 4% have pathogenic variants in TGFβR2, TGFβR1, FBN1, SMAD3, MYH11, or MYLK.
Available Connective Tissue Disorder Panel Tests
Familial Thoracic Aortic Aneurysm and Aortic Dissection (TAAD) Panel – 9 genes
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|ACTA2||Actin, Alpha-2, Smooth Muscle, Aorta||102620||10q23.31|
|COL3A1||Collagen, Type III, Alpha-1||120180||2q32.2|
|MYH11||Myosin, Heavy Chain 11, Smooth Muscle||160745||16p13.11|
|MYLK||Myosin Light Chain Kinase||600922||3q21.1|
|SMAD3||Mothers Against Decapentaplegic, Drosophila, Homolog of, 3||603109||15q22.33|
|TGFβ2||Transforming Growth Factor, Beta-2||190220||1q41|
|TGFβR1||Transforming Growth Factor-Beta Receptor, Type I||190181||9q22.33|
|TGFβR2||Transforming Growth Factor-Beta Receptor, Type II||190182||3p24.1|
The Familial Thoracic Aortic Aneurysm and Aortic Dissection (TAAD) panel should be ordered for individuals with a clear diagnosis of TAAD. The TAAD sub-panel should NOT be ordered for individuals with syndromic features of a connective tissue disorder.
The Connective Tissue Disorders Panel is best suited for individuals with syndromic features of a connective tissue disorder or those who have already exhausted current testing options. However, interpretation of a novel variant may be more difficult if it is found in a gene that is not (yet) known to cause the individual’s clinical diagnosis.
This test is performed by next generation sequencing using Agilent SureSelect capture followed by sequencing of the coding regions and splice sites using Illumina sequencing technologies. Variant calls are generated using the Burrows-Wheeler Aligner followed by Genomic Analysis Tool Kit (GATK) analysis. Detection of copy number variants (CNVs) encompassing 1 or more exons is performed using VisCap™ analysis. Sanger sequencing is used to fill in regions with insufficient coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR. Variants classified as likely benign or benign are not confirmed. This test does not detect variants in non-coding regions that could affect gene expression, aside from the splice junctions. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases.
The proportion of individuals with TAAD who have a deletion/duplication of one of these genes is currently unknown. For comprehensive deletion/duplication analysis of FBN1 (via VisCap or MLPA), please order the Connective Tissue Disorders panel.
Analytical and Clinical Sensitivity
This test is 100.00% sensitive (525/525 variants tested; 95% CI = 99.27-100.00% ) to detect variants changing a single base and 100.00% sensitive to detect insertion/deletions 1-21 bp in size (17/17 variants tested; 95% CI = 81.57-100.00%). Regions with high sequence homology are included in this test if a unique Sanger sequencing assay can be designed to rule out false positive calls. Analytical sensitivity in these regions may be reduced.
The overall detection rate of pathogenic variants is, approximately 10-14% for ACTA2, approximately 4% for TGFβR2, approximately 2% for SMAD3, approximately 1% for TGFβR1, approximately 1% for MYH11, approximately 1% for MYLK, and approximately 1% for FBN1 for individuals with familial thoracic aortic aneurysms or dissections. The detection rate for the remaining genes is currently unknown.